Phase I study of daily administration of MGCD265 to patients with advanced malignancies (Study 265–101)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14525-e14525 ◽  
Author(s):  
C. K. Kollmannsberger ◽  
H. Hurwitz ◽  
G. Vlahovic ◽  
C. Maroun ◽  
J. Dumouchel ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Tumor Development ◽  
Daily Administration ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Grade 3

e14525 Background: MGCD265 is a novel multitargeted receptor tyrosine kinase (RTK) inhibitor that targets the mesenchymal epithelial transition (c-Met) and the vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, and VEGFR3). Additional RTK targets include Tie-2, and Ron. Those kinases are known to be involved in tumor development and angiogenesis. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of daily administration of MGCD265 in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered as a continuous 21-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Ten patients with advanced solid tumors have been treated. Characteristics: age range 25–75; gender: 8 M/2F; ECOG: 0 (1 patient); 1 (9 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs during cycle 1 have been reported. Eight patients received treatment for 2 cycles or more. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax with an approximate mean half-life of 23 hours (see Table below). At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Daily oral administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Further dose escalation is underway. [Table: see text] [Table: see text]

Phase I study of MGCD265 administered intermittently to patients with advanced malignancies (Study 265–102)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14516-e14516
Author(s):  
D. Hong ◽  
P. LoRusso ◽  
R. Kurzrock ◽  
C. Maroun ◽  
M. Mehran ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Open Label ◽  
Dose Escalation Study ◽  
Nonhematologic Toxicity ◽  
Advanced Malignancies ◽  
Label Dose ◽  
Grade 3 ◽  
Age Range

e14516 Background: MGCD265 is an orally-available small molecule designed to inhibit c-Met, VEGFR-1, -2, -3, Tie-2 and Ron kinases. These targets are potentially relevant for the treatment of a variety of cancers. The objective of this Phase I study is to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of MGCD265 using an intermittent schedule of administration in patients with solid tumors. Methods: This is a multicenter, open-label, dose escalation study of oral MGCD265 administered on days 1–7 and 15–21 (1 week on, 1 week off schedule) of each 28-day cycle. Cohorts of 3–4 patients were enrolled per dose level, initially with dose doubling between cohorts, followed by smaller increments once grade 2 drug-related toxicity is observed. Dose limiting toxicity (DLT) was defined as: grade 4 neutropenia; grade 4 thrombocytopenia; any > grade 3 nonhematologic toxicity; severe/sustained hypertension; or any toxic effect leading to a patient missing > 4 doses of MGCD265. Treatment would continue until disease progression or toxicity. Results: Eleven patients with advanced solid tumors have been treated. Characteristics: age range 40–72; gender: 3 M/8F; ECOG: 1 (7 patients); 2 (4 patients). At dose levels of 24, 48 and 96 mg/m2, no DLTs nor grade 2 or greater drug-related AEs have been reported during cycle 1. Six patients received treatment for 2 or more cycles. Preliminary PK profile after the first dose of administration shows a dose dependent increase in AUC and Cmax (Table below) with an approximate mean half-life of 30 hours and an approximate mean Tmax of 7 hours. At the 96 mg/m2 dose, exposure was in the range of the lower end of the efficacious exposure in certain xenograft models. PD markers including plasma HGF and VEGF and shed/soluble receptors s-Met and s-VEGFR2 have been evaluated. Conclusions: Intermittent administration of MGCD265 was found to be well tolerated at doses of 24, 48, and 96 mg/m2. Treatment of patients at 192 mg/m2 is underway. [Table: see text] [Table: see text]

Phase I, open-label, dose-escalation study of AZD7762 in combination with irinotecan (irino) in patients (pts) with advanced solid tumors.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 3033-3033 ◽  
Author(s):  
A. L. Ho ◽  
J. C. Bendell ◽  
J. M. Cleary ◽  
G. K. Schwartz ◽  
H. A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

scholarly journals A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors

2012 ◽  
Vol 31 (2) ◽  
pp. 409-416 ◽  
Author(s):  
Michael S. Gordon ◽  
David S. Mendelson ◽  
Mitchell Gross ◽  
Martina Uttenreuther-Fischer ◽  
Mahmoud Ould-Kaci ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Oral Treatment ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Once Daily ◽  
Label Dose

scholarly journals A Phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors

2012 ◽  
Vol 31 (2) ◽  
pp. 399-408 ◽  
Author(s):  
John Marshall ◽  
Jimmy Hwang ◽  
Ferry A. L. M. Eskens ◽  
Herman Burger ◽  
Shakun Malik ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

scholarly journals Phase I, multicenter, open‐label, dose‐escalation study of sonidegib in Asian patients with advanced solid tumors

2016 ◽  
Vol 107 (10) ◽  
pp. 1477-1483 ◽  
Author(s):  
Hironobu Minami ◽  
Yuichi Ando ◽  
Brigette Buig Yue Ma ◽  
Jih‐ Hsiang Lee ◽  
Hiroyuki Momota ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Asian Patients ◽  
Label Dose

A phase I, open-label, dose-escalation study of the novel oral proteasome inhibitor (PI) ONX 0912 in patients with advanced refractory or recurrent solid tumors.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 3075-3075 ◽  
Author(s):  
K. P. Papadopoulos ◽  
D. S. Mendelson ◽  
A. W. Tolcher ◽  
A. Patnaik ◽  
H. A. Burris ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
The Novel ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of a novel treatment with promising activity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Andrew Eugene Hendifar ◽  
Sant P. Chawla ◽  
Doris Quon ◽  
Victoria S Chua ◽  
Lita Fernandez ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Grade 3

3015 Background: BPM 31510 is a novel small molecule that targets the metabolic machinery of the cancer microenvironment to reverse the aerobic glycolytic phenotype of cancer cells. Effector downstream signaling results in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR Meeting Abstracts 2011). Methods: A standard 3+3 phase I, dose-escalation study design was used in patients with advanced solid tumors refractory to standard treatment. Primary objectives were establishment of the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK) correlates. Secondary objectives included exploratory pharmacodynamics (PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with advanced cancer who had failed multiple chemotherapeutic regimens had been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg). Patients received a median of 2 cycles (1-7). 2 patients have had grade 3 elevation in PT/INR, otherwise there have been no grade 3/4 treatment related toxicities to date. The pharmacokinetics of BPM 31510 are linear and there were no sex differences in the parameters normalized by dose and body surface area. Tmax and Cmax are associated with the end of the infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no dependence of t1/2 on dose. Objective tumor responses have been noted at the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1 minor response (pleomorphic sarcoma). Six patients (19%) have had disease stabilization (> 4 months). Conclusions: Interim data from this phase I study indicate that BPM 31510 is well tolerated with no dose limiting toxicities to date. A partial response and minor response were observed and correlates with dose escalation. Taken together, there is strong rationale for further clinical development of this compound as an anti-cancer agent.

A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3026-3026 ◽  
Author(s):  
Nicolas Isambert ◽  
Antoine Hollebecque ◽  
Yann Berge ◽  
Hein van Ingen ◽  
Silvano Brienza ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Hsp90 Inhibitor ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

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